(±)-lofexidine (1), an imidazoline with α2-adrenergic agonist properties is clinically utilized for the purpose of ameliorating symptoms of disorders that stem from abberations in the α2-adrenoreceptor function. For example, (±)-lofexidine has been used as an anti-hypertensive and for treating the physical and psychological symptoms of opiate abstinence in opiate-addicts (Wilkins, et al., Clin. Pharmacol. Ther. 1981, 30, 752-757; and Akhurst, Pharmacoepidemiology and Drug Safety 2000, 9, 43-47).

The pharmacological properties of (±)-lofexidine are evident upon the interaction of lofexidine either with α2 adrenergic receptors or with any other macromolecule. These pharmacological properties are the result of the individual properties of its two enantiomeric forms, (+)-lofexidine (2) and (−)-lofexidine (3). These chemically distinct entities differ in their affinities toward α2-adrenergic receptors. (−)-lofexidine shows about a 10-fold higher affinity than that of (+)-lofexidine when both are individually pitted against the known α2-adrenergic ligand, 3[H]-clonidine, for competitive displacement from the receptor. This difference between (+)-lofexidine and (−)-lofexidine is mirrored in their unequal capacity to lower mean arterial blood pressure; the effect of (+)-lofexidine is apparent at doses as low as 561 ng/kg, while that of (−)-lofexidine is not seen even at doses as high as 10 μg/kg (Wilffert, et al., Arch. Int. de. Pharmcodynamie et de Ther. 1985, 273, 18-32). (±)-lofexidine is useful in the treatment of hypertension, as well as in the treatment of withdrawal symptoms in opiate addicts. Accordingly, the enantioselective synthesis and usage of solely (−)-lofexidine has been attempted. Three distinct approaches toward the synthesis of (−)-lofexidine are well known, and are described below.
Optical resolution of (±)-lofexidine into (+)-lofexidine and (−)-lofexidine. In the work of Biedermann et. al., (+) and (−)-dibenzoyl tartaric acids are reacted with (±)-lofexidine and subsequently allowed to crystallize from acetone (Biedermann et al., J. Med. Chem. 1986, 29, 1183-1188). After a total of 4 recrystallizations, optically pure (+)-lofexidine is obtained (where (+)-tartaric acid is employed) and (−)-lofexidine is obtained (where (−)-tartaric acid is employed). However, the overall yield of this resolution process is typically 5-10%, making this methodology impractical for large scale preparation.
Enantioselective approach toward (+)-lofexidine and (−)-lofexidine based on amide dehydration, nitrile alcoholysis and imidazoline formation: Another approach described in the work of Biedermann et. al. employs chirally pure ethyl lactate as a starting material. The synthesis (Scheme 1) involves a two-step inversion of the α-chiral center of ethyl lactate followed by amidation, dehydration of the amide, alcoholysis of the resulting nitrile and conversion of the resulting imino-ether into imidazoline followed by salification by anhydrous HCl. An overall yield of 5% is obtained after 8 synthetic transformations that employ two high-vacuum distillation processes.

Enantioselective approach toward (+)-lofexidine and (−)-lofexidine based on Lewis-acid mediated imidazoline formation: U.S. Pat. No. 4,518,783 is directed to a synthetic route toward chirally pure lofexidine (Scheme 2) that begins from intermediate 6 of scheme 1. Amidation with ethylene diamine is followed by Lewis-acid mediated cyclization to imidazoline. An overall yield of 4% is obtained over 5 synthetic transformations that involve a silica-gel column chromatography process following the Lewis-acid mediated imidazoline formation.

The synthesis of a related imidazoline; m-nitrobiphenyline, is also known. (Crassous et al., J. Med. Chem. 2007, 50, 3964-3968). Shown in Scheme 3, a Mitsonubu inversion of the α-hydroxy function of methyl lactate yields an analog of 6. The resulting substituted methyl ester 20 is converted to an imidazoline by heating it with ethylene diamine in dry toluene in the presence of AlCl3. This approach fails to yield a chirally pure product, as the enantiomeric excess was found to be 72%.

Thus, new methods for synthesizing (+) and (−) lofexidine are needed, which provide greater yields than the processes known in the art, and which improve the ease and improves the overall ease and yields of the process, without harm to the stereochemical integrity of the product.